Gastric ulcer is an open sore or raw area in the lining of the stomach. The most common cause of this disease is the infection of the stomach by bacteria called Helicobacter pylori. Most people with gastric ulcer have these bacteria in their digestive system. Yet many people having these bacteria in their stomach do not develop an ulcer. There are several exogenous factors such as excessive alcohol consumption, regular intake of non-steroidal anti-inflammatory drugs (NSAID), cigarette smoking, tobacco chewing, radiation treatment, etc., which lead to hyper-secretion of hydrochloric acid and pepsin followed by hyper-activation of leukotrienes and generation of reactive oxygen species (ROS), causing damage of gastric mucosal layer and initiating ulceration. Then Helicobacter pylori, an opportunistic bacterium, act on the damaged mucosal layer and aggravate the risk of gastric ulcer.
The molecular aspect of gastric ulcer is the pathogenesis which is related to the reduction of mucosal blood flow or a break down in other normal mucosal defence mechanisms in conjunction with injurious effects of acids and malfunctioning or deregulation of various proteases including MMPs in the gastric mucosa.
Small molecule inhibitors of MMPs are known to protect inflammation but give rise to gastric ulcer as severe side effect. See, References 1-3. Recent reports on the development of resistance to such compounds emphasize the need for further therapeutic development to control gastric inflammation. See, References 4, 5. It has been reported that indomethacin is a nonsteroidal anti-inflammatory drug with potent antipyretic, analgesic, and anti-inflammatory activity. It has been effectively used in the management of mild-to-moderate pain since the mid-1960s. It is commonly prescribed for the relief of acute gouty arthritis pain, but has demonstrated efficacy in the treatment of various other painful conditions (Postgrad Med., 2014, 126, 4, 92). Melatonin also belongs to NSAIDs which binds to the catalytic domain of MMP-9 and interacts with the key active site residues of this protease. Understanding the comprehensive molecular structure and the conformational changes of MMP-9 in its inhibited state may aid in the rational design of anti-ulcer/anti-inflammatory drugs. See, References 6-8.
Modern therapeutics for the treatment of gastric ulcer and other inflammatory diseases involve the use of antibiotics, such as amoxicillin, tetracycline, and metronidazole/clarithromycin, along with ranitidine, bismuth citrate and bismuth subsalicylate. Gastric acid suppression by H2 blockers or proton pump inhibitor in conjunction with the antibiotics helps alleviate ulcer-related symptoms (i.e., abdominal pain, nausea) and heals gastric mucosal inflammation by enhancing the efficacy of antibiotics against H. pylori at the gastric mucosal surface. Currently, eight H. pylori treatment regimens are approved by the Food and Drug Administration (FDA). However, several other combinations have been used successfully. Antibiotic resistance and patient noncompliance are the two major reasons for treatment failure.